Targeted interleukin 2 therapy enhances protective immunity induced by an autologous oral DNA vaccine against murine melanoma

We demonstrate that a mouse-human chimeric anti-ganglioside GD2-interleukin (IL)-2 fusion protein (ch14,18-IL2) substantially amplifies tumor-protecti ve immunity against murine melanoma induced by an autologous oral DNA vacci ne containing the murine ubiquitin gene fused to murine melanoma peptide ep itopes gp100(25-35) and TRP-2(181-188). This combination therapy led to the complete rejection of a lethal challenge with B78D14 murine melanoma cells in six of eight mice and a marked suppression of s.c. tumor growth in the two remaining animals. The tumor-protective immunity was mediated by MHC cl ass I antigen-restricted CD8(+) T cells together with CD4(+) T cell help, w hich was required only for tumor cell killing in the effector phase of the immune response. A single oral vaccination with the DNA vaccine, which was carried by attenuated Salmonella typhimurium, was equally as effective as t hree such vaccinations applied at 2-week intervals. The immunological mecha nisms involved in this antitumor effect were suggested by a decisively incr eased secretion of tumor necrosis factor alpha TNFTnTNa and IFN-gamma from CD4(+) and CD8(+) T cells and a markedly up-regulated expression on CD8' T cells of high-affinity IL-2 receptor alpha chain (CD25), costimulatory mole cule CD28, and adhesion molecule lymphocyte function-associated antigen-2 ( LFA-2/CD2). Additionally, the combination therapy induced increased express ion of costimulatory molecules B7.1 and CD48 on murine antigen-presenting c ells. Taken together, our results suggest that IL-2 targeted to the tumor m icroenvironment by a specific antibody-IL-2 fusion protein is a potent enha ncer of tumor-protective immunity induced by an oral DNA vaccine that may u ltimately enhance the chances of success in its clinical application.